The present invention pertains to methods of immunotherapy for treating cellular Fc receptor mediated immune disorders in humans and animal by altering the endogenous Fc receptor mediated immune response in the body by administration of an exogenous polypeptide having a cellular Fc receptor-like binding capability for endogenous antibodies and antibody-antigen immune complexes.
The basic principles of immunology pertaining to immunotherapy are presented in the clinical medical art, for example: The Merck Manual of Diagnosis and Therapy, (thirteenth edition, 1977). R. Berkow and J. H. Talbott (eds.), "Immunology Allergic Disorders", pp. 183-156. Merck & Co., Rahway, N.J.; and Basic & Clinical Immunology (sixth edition, 1987) D. P. Stites, J. D. Stobo and J. V. Wells (eds.), Appleton & Lange, Los Altos, Calif. These basic principles of immunology are stated as follows.
The human and animal body develops immunity against a variety of invading agents by producing antibody mediated humoral immunity or sensitized cell mediated cellular immunity capable of reacting with and destroying the invading agent. Any agent that can elicit an immune response in the body is called an antigen. Examples of antigens includes: infectious agents, e.g. bacteria and viruses; drugs, e.g. antibiotics; toxins, e.g. chemical substances; foreign tissues, e.g. transplantation antigens; and various self-tissues, e.g. autoimmune antigens, cancer cells, and idiotypes of antibodies. The primary functions of the immune response toward an antigen are recognition, specific response, clearance and memory. In order for the immune system to identify, specify, neutralize and memorize the antigen, immune cells must develop and differentiate to achieve competent cellular and humoral immunity toward the antigen. Regulation or amplification of the immune response in either a positive or negative fashion occurs through cell populations such as T helper and T suppressor lymphocytes and interaction between humoral factors such as antibody, antigen-antibody immune complex, cytokines, e.g. interferons, interleukins, and cellular receptors for those humoral factors, e.g. Fc receptors.
Exposure of a human or animal to a given antigen activates the immune system to develop specific antibodies against the antigen. Antibodies which circulate in the body liquids (humoral immunity) are capable of combining with the antigen forming an antigen-antibody immune complex, wherein the antigen may be inactivated and/or subsequently destroyed. Furthermore, a cellular immunity can be developed by formation of sensitized cells, e.g. sensitized leukocytes, which contain "antibodies", e.g. receptors against the particular antigen, attached to the cell wall and which are capable of combining with the antigen in an immunological reaction and subsequently inactivating and/or destroying it.
Fc Receptors and Fc receptor mediated immunity and immune regulation are well known in the immunological literature, for example: Structure and Function of Fc Receptors (1983), A. Froese and F. Paraskevas (eds.), Marcel Dekken, Inc., New York.; Cowan, F. M., et al., 1980, Biomedicine 32, 108; and Kerbel, R. S. & Davies, A. J. S., 1974, Cell 3, 105. Certain body cells, e.g. lymphocytes and macrophages, possess in their cell walls Fc receptors capable of binding with a specific binding site in the antibody molecule e.g. Fc-fragment, Fc-constant region. Cellular Fc receptors are capable of binding free antibodies and/or antigen-antibody complexes to the cell wall. Cellular Fc receptors may also be secreted and circulate in humoral fluids as "Immunoglobulin binding factors". Cellular Fc receptor mediated immune responses and immunity are regulated by the attachment of free antibodies or immune complexes to the cellular Fc receptors Sinclair, N. R., 1978, Transplant. Proc. 10, 349 and Sinclair, N. R. and Panoskaltsis, A., 1987, Immunol. Today 8, 76. Since both antigen-antibody immune complex and free antibody compete for attachment to the cellular Fc receptor, the amount and type of free antibodies or immune complexes which become attached and thus the degree of the subsequent cellular Fc receptor mediated immune response may vary dependent on the ratio between free antibodies and antigen-antibody immune complexes and Fc receptors which are present in the given Fc receptor mediated immune reaction.
Antibody binding antigen to the variable antigen-binding site on the Fab portion of the antibody molecule provides antigen specificity; whereas, the antibody Fc constant region engaging Fc receptors activates Fc receptor mediated immunity towards the antigen and transport of antibody across membranes, e.g. delayed hypersensitivity, antibody dependent cellular cytotoxicity (ADCC). Structure and Function of Fc Receptors, 1983, A. Froese and F. Paraskevas (eds.), Marcel Dekken, Inc.: New York.); Cowan, F. M., et al., 1980, Biomedicine 32, 108. Antigen specific coordination of the immune response to antigen orchestrated by the antigen independent binding of a single molecule, e.g. Fc receptor, explains how a single molecule, e.g. the Fc receptor can control immunity to an infinity of antigens (Sinclair, N. R., 1978, Transplant. Proc. 10, 349; Sinclair, N. R. and Panoskaltsis, A., 1987, Immunol. Today 8, 76; and provides the opportunity to alter Fc mediated immunity to any antigen, by administering exogenous Fc receptors to change the ratio of endogenous Fc receptors to Fc receptor binding molecules e.g. antibody, antigen-antibody immune complex (Cowan, F. M., et al., 1980, Biomedicine 32, 108; Cowan, F. M., et al., 1982, Biomedicine 36, 29).
The mechanism of Fc receptor mediated immunity to antigen is constant for all antigens, for example, sheep red blood cell which is a standard test antigen for assaying immunity (present application Examples 1 and 2), (Cowan, F. M., et al., 1979. Biomedicine 30, 23), (Cowan, F. M., et al., 1979, Biomedicine 30, 241) or antigen of a disease related to the immune response, wherein insufficient immunity to antigen, e.g. cancer cell antigen is known to contribute to the pathology of the disease e.g. adenocarcinoma (present application Example 7), (Cowan, F. M., et al., 1982, Biomedicine 36, 29). Therefore, internal use of an exogenous Fc receptor to alter endogenous Fc receptor mediated immunity to antigen is useful in the treatment of diseases related to the immune response, wherein abnormal Fc receptor mediated immunity to antigen contributes to the pathology or symptom of the disease. It (systemic exogenous Fc receptor immune therapy) is the major method of the present invention.
Many pathological disorders in humans and animals involve undesirable or abnormal cellular Fc receptor mediated immune responses, including insufficient or excessive immune responses towards antigens, Cowan, F. M., et al., 1980, Biomedicine 32, 108 and Cowan, F. M., et al., 1982, Biomedicine 36, 29. Diseases related to the immune response, wherein abnormal immunity to antigen causes or contributes to the pathology or symptoms are documented and described in the clinical medical art. The Merck Manual of Diagnosis and Therapy (thirteenth edition 1977) devotes section 2 (pages 183-255) to immunology and allergic disorders; these diseases related to the immune response include: infectious agents, e.g. virus and bacteria; immunodeficiency diseases; hypersensitivity reactions, e.g. delayed hypersensitivity; autoimmune disorders; transplantation; and tumor immunology. Furthermore, the basic principles and participating molecules, e.g. antibody, immune complex, Fc receptors, and cytokines are the same for humans and other mammals, e.g. veterinary and laboratory animals. See An Introduction To Veterinary Immunology (1977), Ian R. Tizard; W. B. Saunders Company, Philadelphia; and Basic & Clinical Immunology (sixth edition, 1987), D. P. Stites, J. D. Stobo and J. V. Wells (eds.), Appleton & inventionLange, Los Altos, Calif. The Merck Veterinary Manual (sixth edition, 1986), C. M. Fraser (ed.), "The Immune System" pp. 409-424, Merck & Co., Rahway, N.J., describes diseases relating to the immune response in animals which correspond with human diseases related to the immune response listed in The Merck Manual of Diagnosis and Therapy, (thirteenth edition, 1977). Furthermore, there are "standards tests" for determining immunity to antigen (The Merck Manual of Diagnosis and Therapy, thirteenth edition, 1977). Principles for the use of drugs affecting the immune response are described; e.g. as to corticosteriods Merck Manual, 1977, states at page 1903: "8. All dosages should be individualized. The effective dose varies with different diseases, with different phases of the same disease, and from patient to patient. 9. The dosage should be kept flexible, being raised or lowered according to alterations in the course of the disease or the development of undesirable effects."
The physiological immune responses are designed to eliminate or neutralize antigens. The formation of antigen-antibody immune complexes is a crucial component in the normal defense of the body again pathogens and other antigens. Under some circumstances, e.g. immune complex disease, immune complexes circulating in the body fluids become pathogenic and may induce inappropriate activation or inactivation of humoral or cellular immunologic effectors. Agnello, V., Manual of Clinical Immunology, Rose, N. R. and Friedman H. (eds.), American Society For Microbiology, Washington D.C., p. 178, 1980. Immune complex can also deposit in the tissues of various organs activating effector cells and/or complement, a group of sera proteins that can penetrate and damage cell walls, resulting in the release of substances that produce inflammation and tissue injury. Immune complexes have been associated with glomerulonephritis and vasculites for a wide variety of disease states including bacterial, viral and parasite infections, as well as autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematoses.
Immune complex disease associated with diseases related to the immune response, wherein the immune complex disease causes or contributes to abnormal Fc receptor mediated immunity to disease antigen, e.g. antibody dependent cellular cytotoxicity (ADCC) and delayed hypersensitivity, is documented in the medical art. See Cowan, F. M., et al., 1980, Biomedicine 32, 108; The Merck Manual of Diagnosis and Therapy (thirteenth edition, 1977, pp. 183-255; Spitler, L. E. p. 200, 1980, Manual of Clinical Immunology, Rose, N. R. and Friedman H. (eds.), American Society For Microbiology, Washington D.C. Clinical tests to determine immune complex and Fc receptor mediated immunity are available and described in the clinical medical art. These include the ADCC assay (Example 1 of the present application). See Schur, P. H., p. 193, 1980, Manual of Clinical Immunology, Rose, N. R. and Friedman H. (eds.), American Society For Microbiology, Washington D.C. Immune-complexes consisting of tumor antigens and antibodies have been identified in the sera of patients with various malignancies. There is convincing evidence that tumor antigen-antibody complexes interfere with the lymphocyte functions that would normally destroy the tumor cells Cowan; F. M., et al., 1979, Biomedicine 30, 23; Messerschmidt et al., 1988, J. Clin. Oncol., 6, 487.
An association between bacterial infection, or immunotherapy with bacterial products, and tumor regression is described in the medical art (Old, L. J., 1988, Scientific American 258, 59; Cowan, F. M., et al., 1980, Biomedicine 32, 108; Nauts H. C., 1977, Develop. Biol. Standard 38, 487). This association may be summarized as follows: For centuries spontaneous tumor regressions have been associated with microbial infection, principally Staphylococcal and Steptococcal. Bush, in 1868, documented spontaneous tumor regression occurring in patients with erysipelas infection due to Streptococcal organisms. Dr. William Bradley Coley, a surgeon at Memorial Hospital in New York, from 1897-1931, treated cancer patients with microbial products and achieved numerous remissions of a variety of cancers. "Coley's toxins" consisted of a mixture of two microbes, Streptococcus pyogenes and Serratia marcescens. Although Dr. Coley results were dramatic, with remissions of histologically confirmed inoperable cancers, the crude bacterial preparations and lack of knowledge of the immune system prevented identifying the active components and mode of anticancer action.
A "rational basis" for the antineoplastic activity of Coley's toxins can be presented based on contemporary knowledge of cytokine and Fc receptor immunotherapy. Coley may have nearly a century past used a form of combined cytokine-Fc receptor synergistic immunotherapy. Interferons (IFN), Interleukins (IL) and tumor necrosis factor (TNF) are cytokines and all three substances have displayed individual anticancer activity in human clinical trials (Old, L. J., 1988, Scientific American 258, 59), (Ravin, A., et al., 1988, Can. Res., 48, 2245), (McIntosh, J. K., et al., 1989, Can. Res., 49, 1408). Furthermore, when used in combination against mouse sarcoma metastatic tumors, as a immunotherapeutic prototype for human clinical trials, they display synergism in that the cytokines are much more effective, even at lower nontoxic doses, used in combination than individually (Ravin, A., et al., 1988, Can. Res., 48, 2245), (McIntosh, J. K., et al., 1989, Can. Res., 49, 1408).
The injection of combined Serratia marcescens and Streptococcus pyogenes microbial products have induced IFN and IL in cancer patients (Axelrod, R. S., et al, 1988, Cancer 61, 2219). The Serratia marcescens the gram negative microbial component of Coley's toxins contains lipopolysaccharide (LPS), the most potent inducer of TNF (Old, L. J., 1988, Scientific American 258, 59), and peptidoglycans, which contain muramyl peptides which are associated with IL-like activity (Chedid, L., 1986, Fed. Proceed., 45, 2531), (Kotani, S., et al, 1986, Fed. Proceed., 45, 2534). LPS (Old, L. J., 1988, Scientific American 258, 59) and muramyl peptide (Chedid, L., 1986, Fed. Proceed., 45, 2531) have demonstrated individual and combined synergistic antineoplastic activity (Fuks, B. B., et al., 1987, Byulleten' Eksperimental'noi Biologii i Meditsiny, 104, 497); furthermore, both LPS and muramyl peptide induce the cytokines INF and TNF with their combined action on INF and TNF production being synergistic (Kotani, S., et al., 1986, Fed. Proceed., 45, 2534), (Fuks, B. B., et al., 1987, Byulleten' Eksperimental'noi Biologii i Meditsiny, 104, 497). INF, IL, and TNF combined cytokine immunotherapy may explain the antineoplastic action of the Serratia marcescens component of Coley's toxins.
The major antineoplastic component of Coley's toxins Streptococcus pyrogenes, and certain other gram positive microbes such as Staphylococcus aureus, in addition to muramyl peptides (Kotani, S., et al, 1986, Fed. Proceed., 45, 2534) associated with IL-like activity, contain in their cell walls proteins which bind the Fc constant region of antibody, e.g. exogenous Fc receptors (Boyle, M. P. D., and Reis, K. J., 1987, Bio/Technology 5, 697). Cytokines, e.g. interferon, enhance Fc receptor expression amplifying Fc receptor mediated immunity (Cowan, F. M., et al., 1982, Biomedicine 36, 29), and Fc receptors, engaged by antibody Fc constant region ligand, function as signal transducing molecules which promote gene expression and production of cytokines (Cassatella, M. A., et al., 1989, J. Exp. Med., 169, 549) indicating a Fc receptor-cytokine immune regulatory loop. A Fc receptor-cytokine immune regulatory loop provides a "rational basis" for the synergistic actions of the cytokine inducing and microbial Fc receptor components of Coley's toxins. The implications that Coley's toxins contained immunotherapeutic bacterial molecules such as muramyl peptide and LPS that either mimic or induce a variety of cytokines and bacterial Fc receptor which acted in a synergistic fashion to stimulate the bodies immune response to destroy cancers provides the medical art with a historical "rational basis" for bacterial product, e.g. microbial Fc receptor, muramyl peptides, LPS or combination of bacterial products for immunotherapy of cancer. It is a particular advantage of the present invention that exogenous Fc receptor systemic immunotherapy can be used in conjunction with other immune modulators such as microbial products or cytokines to achieve synergistic immunotherapy.
Several studies concerning the influence of staphylococcus aureus protein A (which in the following will be abbreviated as SPA) on immune-reactions have been made and a variety of contradictory in vitro results have been reported. These include activation of ADCC (Sulica, A., et al., 1976, Scand. J. Immunol., 5, 1192), inhibition of ADCC (Rossenblatt, J., et al., 1977, J. Immunol. 118, 981), mitogenic activity (Forsgren, A., Eur. J. Immunol., 1976, 6, 207-218, and anti-mitogenic activity (Williams, R. C. and Kronvall, G., 1972, Proc. Soc. Exp. Biol. Med., 139, 480). The publications of Cowan et al. harmonizes these contradictory results described in the prior scientific art and present the concept of exogenous Fc receptor systemic immunotherapy, for example: (1) The augmentation or inhibition of ADCC by SPA in vitro was shown to be due to the relative ratio of antibody, immunecomplex and Fc receptor (1979, Biomedicine 30, 23), (present application Example 1). (2) SPA augments or inhibits immunity, e.g. delayed hypersensitivity to antigen, such as SRBC in vivo (1979, Biomedicine 30, 241), (present application Example 2). (3) The mitogenic and antimitogenic activity of SPA is due to the Fc receptor valence (1979, Biomedicine 31, 220), (present application Example 3). (4) A review article explaining the use of exogenous Fc receptors to alter endogenous Fc receptor mediated immunity (1980, Biomedicine 32, 108). (5) systemic SPA Immunotherapy of rat adenocarcinoma (1982, Biomedicine 36, 29). (present application Example 7). Staphylococcus aureus Cowan I whole bacteria has been used in vitro to remove "blocking activity" from tumor-bearer sera (Steele, G., et al., 1975, Int. J. Cancer 15, 180), and ex vivo on affinity columns (extracorporeal perfusion) to treat a single colon carcinoma patient (Bansal S. C., et al., 1978, Cancer 42,1); however, no systemic, e.g. oral or parenteral, in vivo pharmaceutical use of SPA has been suggested prior to the publications of Cowan et al. The systemic exogenous Fc receptors immunotherapy, the method of the present invention, provides a particular advantage over the more expensive and invasive ex vivo extracorporeal perfusion immunotherapy.
Pollard U.S. Pat. No. 4,464,164. Oct. 11, 1983) teaches that the ex vivo extracorporal Fc-reagents can be used to retard the growth of neoplasts in subject mammals and the utility for the use of an extracorporal Fc-reagent to retard the growth of neoplasts is established by reference to published prior art (col. 1, lines 9-19). The advantage over the prior blood processing art claimed in the Pollard patent is that no separation of plasma from other blood elements is required which reduces the complexity of the extracorporal procedure (col. 1, lines 36-41). Systemic SPA immunotherapy, the method of the present application, completely eliminates the expensive and invasive extracorporeal procedure and therefore constitutes a great advantage over the prior SPA ex vivo immunotherapy.
Sedlacek et al U.S. Pat. No. 4,479,934 teaches the injection of complement or antibody Fc-reagents for the treatment of immune complex disease. These endogenous Fc receptors produced within the body differ from the exogenous Fc receptors of the present invention which are produced outside the body, e.g. microbial Fc receptors.